The stimulus-controlled pathways of sphingolipid metabolism provide a rich network of bioactive molecules with pivotal roles in the regulation of diverse cell functions. Sphingolipid metabolites, namely ceramide (Cer) and sphingosine 1-phosphate (S1P), are increasingly being recognized for their role as signaling molecules involved in regulation of survival, proliferation and cell death. In particular, the cellular balance between Cer and S1P seems to play a role in a cell's decision to either undergo apoptosis or proliferate, two events which are implicated in tumor development and growth. Whereas Cer possesses pro-apoptotic capacity in many cell types, S1P acts as a counter player able to induce cell proliferation and protect cells from undergoing apoptosis. Therefore, tipping the balance in favor of Cer production, i.e., by inhibiting ceramidase (CDase) or sphingosine kinase (SK) activities has potential to support its pro-apoptotic action and represents a promising rational approach to effective cancer therapy. See Ogretmen and Hannun, Nat. Rev. Cancer, 4, 604-616 (2004); and Huwiler and Zanaemeister-Wittke, Oncology Hematol., 63, 150-159 (2007).
Acid ceramidase (ACDase or AC), a lysosomal enzyme, catabolizes Cer into sphingosine (Sph), a substrate for SK, and free fatty acids at an optimal pH of approximately 4.5, distinguishing it from other CDases. Sph released by the action of ACDase can serve as a substrate for SK to form S1P or as a substrate for ceramide synthases to resynthesize new Cers. See Bielawska et al., Bioorg. Med. Chem., 16, 1032-1045 (2008). ACDase represents a new target for cancer therapy because of its role in regulating the Cer-Sph-S1P inter-metabolism. Levels of ACDase have been shown to be elevated in many tumor cell lines. See Elojeimy et al., Mol. Ther., 15, 1259-1263 (2007). Inhibition of ACDase activity leads to elevation of intracellular C16-, C14, and C18-Cers, decrease of Sph and S1P, and stimulation of apoptotic cell death. See Bielawska et al., Bioorg. Med. Chem., 16, 1032-1045 (2008). Thus, ACDase has become a target in cancer therapy, and its inhibitors act as chemotherapeutic agents on several types of cancers. See Liu et al., Front. Biosci., 13, 2293-2298 (2008); and Szulc et al., Bioorg. Med. Chem., 16, 1015-1031 (2008).
Accordingly, there is an ongoing need for novel ACDase inhibitors, ideally having one or more of the following properties: easily delivered to cells, accumulate preferentially in the lysosomal compartment where ACDase is present, and do not cause permanent damage to the lysosomal compartment.